Expression of proteins related to autotaxin–lysophosphatidate signaling in thyroid tumors

Autotaxin (ATX) is a glycoprotein transcribed by the ENPP2 gene on chromosome 8 [1]. ATX is the same molecule as lysophospholipase D and converts lysophosphatidylcholine (LPC) to bioactive lipid mediator lysophosphatidate (LPA). LPA, after binding to the appropriate receptor, activates phospholipase C and the MAPK, PI3K, and RhoA pathways and is involved in various cellular processes [2, 3]. LPA receptor is a G-protein-coupled receptor. There are at least six LPA receptors, LPA1 through LPA6. LPA1 through LPA3 belong to the EGD family (i.e., LPA1-EDG2, LPA2-EDG4, LPA3-EDG7), while LPA4 through LPA6 are similar to the P2Y nucleotide receptor [4]. This ATX–LPA signaling is involved in tumor formation, progression, and metastasis [5, 6].

Thyroid cancer is a relatively common malignancy, affecting about 1% of the population. The most common histologic type of thyroid cancer is papillary thyroid carcinoma (PTC), followed by follicular carcinoma (FC), medullary carcinoma (MC), poorly differentiated carcinoma (PDC), and anaplastic carcinoma (AC). These histologic subtypes of thyroid cancer are known to have different cell origins, clinical manifestations, metastatic patterns, and clinical prognoses. Previously, ATX has been reported to be highly expressed in undifferentiated carcinoma [7], and it is also indicated to be expressed in follicular carcinoma [8]. Furthermore, as ATX expression is higher in thyroid cancer than in benign lesion [9] and is correlated with prognostic factors in thyroid cancer [10], ATX–LPA signaling is likely to have an influence on thyroid cancer biology. However, studies on proteins related to ATX–LPA signaling in recurrent and metastatic thyroid cancer and according to thyroid tumor subtype have not been reported. Thus, we aimed to assess the expression of proteins related to ATX–LPA signaling in recurrent and metastatic thyroid cancer and according to thyroid tumor subtype.

We investigated the expression of proteins related to the ATX–LPA axis in thyroid cancer. First, ATX was more highly expressed in medullary carcinoma than in other subtypes. Previous studies have shown that ATX-related protein expression was higher in thyroid cancer or metastatic thyroid cancer than in normal thyroid tissue or benign thyroid neoplasm [9, 10], but there has not been any report published to date on ATX-related protein expression in thyroid medullary carcinoma. The possible mechanism for the high expression of ATX in thyroid medullary carcinoma is the JAK/STAT3 pathway. In previous studies on breast cancer, activation of the JAK/STAT3 pathway was reported to increase the expression of ATX [12], which is suggested to represent a putative STAT3 target gene. Meanwhile, it has been reported that the JAK/STAT3 pathway is also activated in thyroid medullary carcinoma [13, 14]; consequently, it is only plausible that ATX expression is somehow associated with the JAK/STAT3 pathway. Our study showed that LPA1 was highly expressed in PDC and AC, and that LPA2 and LPA3 were similarly highly expressed in PTC. A previous study on thyroid cancer reported that LPA1 messenger RNA expression showed no difference among normal thyroid tissue, benign thyroid nodule, and thyroid cancer [15]. However, the study had included PTC and FC for thyroid cancer; therefore, its direct comparison with our study, which includes PDC and AC in addition to PTC and FC for thyroid cancer, is not possible. Separately, another previous study suggested CD97 as a dedifferentiation marker in thyroid cancer [16], the expression of which is reported to be correlated with LPA receptor in thyroid cancer [17]. Such a result is related with the high expression of LPA1 in PDC and AC in our study. LPA2 has been previously reported to be highly expressed in PTC, which is in concordance with our results [15]. On the other hand, our study showed low expression of proteins related to the ATX–LPA axis in PTC and FVPTC without BRAF V600E mutation, a result that disagreed with those of the previous study that reported that ATX protein expression is not correlated with BRAF mutation status [9]. Usually, most FVPTC cases do not harbor BRAF V600E mutation; thus, it is necessary to assess the correlation between BRAF V600E mutation and the ATX–LPA axis. The most plausible mechanism is that BRAF V600E mutation activates cytokine release, which in turn increases ATX protein expression. Tumor cells showing BRAF V600E mutation tend to have increased cytokine secretion such as that of interleukin (IL)-1β, IL-6, and IL-8 [18], because cytokines such as tumor necrosis factor alpha or IL-1β increase ATX and LPA levels. In our study, ATX and LPA1 expression was a poor prognosis factor in PTC, which is in concordance with previous study results that had identified ATX as a poor prognosis factor in breast cancer [19] and in prostate cancer [20] and, separately, LPA2 as a poor prognosis factor in breast cancer [21].

The clinical implication of our study is that the ATX–LPA signaling axis may be a possible therapeutic target in thyroid cancer. Ki16425, a nonlipid competitive inhibitor of LPA1 and LPA3, actually suppressed bone metastasis in a mouse model [22]. Debio0719, an R-stereoisomer of Ki16425, was found to inhibit distant metastasis [23, 24]. BrP-LPA, which is a dual ATX and pan-LPAR inhibitor, inhibited cell migration and invasion [25]. In addition, an ATX inhibitor, ONO-843050, decreased tumor volume to 50% to 60% in a mouse model of PTC [9]. Therefore, the ATX–LPA axis may be an effective treatment target for thyroid cancer, and further clinical trials are necessary.

The expression of proteins related to the ATX–LPA axis is different according to tumor subtype and is notably higher in metastatic thyroid cancer than in primary tumor. Furthermore, proteins related to the ATX–LPA axis may represent candidates for effective treatment target in thyroid cancer.